Our earlier work defined and characterized the ability of glucagon, epinephrine, norepinephrine and cortisol to independently stimulate glucose production (glycogenolysis and gluconeogenesis) and ketogenesis in vivo. The aim of the work proposed in this application is to study the interaction of these hormones in the regulation of glucose production and ketogenesis in vivo and, specifically, to delineate their roles in two physiologic circumstances: hypoglycemia and exercise. Experiments will be carried out in overnight-fasted, conscious dogs in which hormone levels and neural outflow are controlled using surgical and pharmacologic methods. To control epinephrine and cortisol levels, adrenalectomy and hormone replacement will be used; to control glucagon and growth hormone concentrations, somatostatin and hormone replacement will be used; and to control neural outflow, the hepatic nerves will be cut and/or the head glucose level will be clamped (glucose infusion into the carotid and vertebral arteries). Glucose production (gluconeogenesis, glycogenolysis) will be measured using tracer and A-V difference techniques, and ketogenesis will be measured using the A-V difference technique. In the first group of studies the role of each counterregulatory hormone in the metabolic response to the hypoglycemia resulting from constant intravenous insulin infusion will be determined. The second set of experiments will define the role neural outflow and local hypoglycemia autoregulation) play in that response. In the third set of studies the ability of hypoglycemia to modify the sensitivity of the liver to the counterregulatory hormones will be assessed. The fourth and fifth sets of studies will determine the role of each counterregulatory hormone in the metabolic response to exercise and the effect of a mild accompanying hypoglycemia on their actions. In the sixth set of studies the by which cortisol modifies the metabolic effects of epinephrine and glucagon will be determined. Finally, the metabolic effects of synchronous and prolonged elevations in the counterregulatory hormones will be determined, and the role of each individual hormone in the overall response will be defined. These studies should further our understanding of the metabolic roles of glucagon, epinephrine, norepinephrine and cortisol in various physiologic circumstances; they should identify the processes activated (glycogenolysis, gluconeogenesis, ketogenesis) and the site (adipose tissue, muscle, liver) at which the stimulation occurs.